An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia

Abstract Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.

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Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – A case report

10.21203/rs.2.307/v1 ◽

2019 ◽

Author(s):

Sofia Thunström ◽

Markus Axelsson

Keyword(s):

Case Report ◽

Peripheral Neuropathy ◽

De Novo ◽

Age Of Onset ◽

De Novo Mutation ◽

Missense Mutations ◽

Dural Ectasia ◽

Whole Exome ◽

Demyelinating Peripheral Neuropathy ◽

Multiple Cysts

Abstract Background: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. Case Presentation: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686T>G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. Conclusions: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes. Keywords: Leukoencephalopathia, demyelinating peripheral neuropathy, dural ectasia explained, de novo mutation, the SAMD9L gene.

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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

10.1101/092346 ◽

2016 ◽

Author(s):

Ricardo Harripaul ◽

Nasim Vasli ◽

Anna Mikhailov ◽

Muhammad Arshad Rafiq ◽

Kirti Mittal ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Autosomal Recessive ◽

De Novo ◽

Clinical Diagnostics ◽

High Yield ◽

Disease Genes ◽

Missense Mutations ◽

Loss Of Function ◽

Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability

Cytogenetic and Genome Research ◽

10.1159/000515368 ◽

2021 ◽

pp. 1-7

Author(s):

Tuğba Karaman Mercan ◽

Ozden Altiok Clark ◽

Ozgur Erkal ◽

Banu Nur ◽

Ercan Mihci ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Array Cgh ◽

De Novo ◽

Homozygous Deletion ◽

Clinical Findings ◽

Chromosome 4 ◽

Heterozygous Deletion ◽

Whole Exome

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the <i>IQSEC2</i> gene in the girl, a variant that is related to X-linked intellectual disability.

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RYR2 Mutations Are Associated With Benign Epilepsy of Childhood With Centrotemporal Spikes With or Without Arrhythmia

Frontiers in Neuroscience ◽

10.3389/fnins.2021.629610 ◽

2021 ◽

Vol 15 ◽

Author(s):

Mei-Gang Ma ◽

Xiao-Rong Liu ◽

Yuan Wu ◽

Jie Wang ◽

Bing-Mei Li ◽

...

Keyword(s):

De Novo ◽

Arrhythmogenic Right Ventricular Dysplasia ◽

Polymorphic Ventricular Tachycardia ◽

Compound Heterozygous ◽

Endoplasmic Reticulum Membrane ◽

Missense Mutations ◽

Unexpected Death ◽

Sinus Arrhythmia ◽

Whole Exome ◽

Benign Epilepsy

RYR2 encodes ryanodine receptor 2 protein (RYR-2) that is mainly located on endoplasmic reticulum membrane and regulates intracellular calcium concentration. The RYR-2 protein is ubiquitously distributed and highly expressed in the heart and brain. Previous studies have identified the RYR2 mutations in the etiology of arrhythmogenic right ventricular dysplasia 2 and catecholaminergic polymorphic ventricular tachycardia. However, the relationship between RYR2 gene and epilepsy is not determined. In this study, we screened for novel genetic variants in a group of 292 cases (families) with benign epilepsy of childhood with centrotemporal spikes (BECTS) by trio-based whole-exome sequencing. RYR2 mutations were identified in five cases with BECTS, including one heterozygous frameshift mutation (c.14361dup/p.Arg4790Pro fs∗6), two heterozygous missense mutations (c.2353G > A/p.Asp785Asn and c.8574G > A/p.Met2858Ile), and two pairs of compound heterozygous mutations (c.4652A > G/p.Asn1551Ser and c.11693T > C/p.Ile3898Thr, c.7469T > C/p.Val2490Ala and c.12770G > A/p.Arg4257Gln, respectively). Asp785Asn was a de novo missense mutation. All the missense mutations were suggested to be damaging by at least three web-based prediction tools. These mutations do not present or at low minor allele frequency in gnomAD database and present statistically higher frequency in the cohort of BECTS than in the control populations of gnomAD. Asp785Asn, Asn1551Ser, and Ile3898Thr were predicted to affect hydrogen bonds with surrounding amino acids. Three affected individuals had arrhythmia (sinus arrhythmia and occasional atrial premature). The two probands with compound heterozygous missense mutations presented mild cardiac structural abnormalities. Strong evidence from ClinGen Clinical Validity Framework suggested an association between RYR2 variants and epilepsy. This study suggests that RYR2 gene is potentially a candidate pathogenic gene of BECTS. More attention should be paid to epilepsy patients with RYR2 mutations, which were associated with arrhythmia and sudden unexpected death in previous reports.

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Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease

Neuropediatrics ◽

10.1055/s-0037-1608921 ◽

2017 ◽

Vol 49 (02) ◽

pp. 118-122 ◽

Cited By ~ 3

Author(s):

Lydia Green ◽

Ian Berry ◽

Anne-Marie Childs ◽

Helen McCullagh ◽

Sandhya Jose ◽

...

Keyword(s):

De Novo ◽

Mutation Screening ◽

Copy Number Variants ◽

Gene Mutations ◽

Fiber Formation ◽

Alexander Disease ◽

Missense Mutations ◽

Gene Encoding ◽

Whole Exome ◽

Filament Network

AbstractAlexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white–gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

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Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – A case report

10.21203/rs.2.307/v2 ◽

2019 ◽

Author(s):

Sofia Thunström ◽

Markus Axelsson

Keyword(s):

Case Report ◽

De Novo ◽

Age Of Onset ◽

De Novo Mutation ◽

Missense Mutations ◽

Case Presentation ◽

Whole Exome ◽

Demyelinating Peripheral Neuropathy ◽

The Brain ◽

Multiple Cysts

Abstract Background: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. Case presentation: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686T>G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. Conclusions: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.

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Wiedemann-Steiner syndrome with a novel pathogenic variant in KMT2A: a case report

Colombia Medica ◽

10.25100/cm.v50i1.3555 ◽

2019 ◽

pp. 40-45 ◽

Cited By ~ 3

Author(s):

Diana Ramirez Montaño ◽

Harry Pachajoa

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Specific Binding ◽

Genetic Disorder ◽

Low Frequency ◽

Clinical Findings ◽

Whole Exome ◽

One Year

Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.

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Whole exome-trio analysis reveals rare variants associated with Congenital Pouch Colon

10.1101/2019.12.10.19013680 ◽

2019 ◽

Author(s):

Sonal Gupta ◽

Praveen Mathur ◽

Ashwani Kumar Mishra ◽

Krishna Mohan Medicherla ◽

Prashanth Suravajhala

Keyword(s):

Rare Variants ◽

De Novo ◽

Anorectal Malformations ◽

Open Reading Frames ◽

Missense Mutations ◽

Clinical Genetic ◽

Variants Of Unknown Significance ◽

Whole Exome ◽

Congenital Pouch Colon ◽

Pouch Colon

AbstractAnorectal malformations (ARM) are individually common but Congenital Pouch Colon (CPC), a rare anorectal anomaly causes a dilated pouch in genitourinary tract. We have earlier attempted to understand the clinical genetic makeup of CPC and identified genes responsible for the disease using whole exome sequencing (WES). Here we report our studies of CPC, by identifying de novo heterozygous missense mutations in 16 proband-parent trios and further discover variants of unknown significance which could provide insights into CPC manifestation and its etiology. Our study confirms candidate mutations in genes, viz. C7orf57, C10orf120, C9orf84 and MUC16, CTC1 particularly emphasizing the role of hypothetical genes or open reading frames causing this developmental disorder. Variant validation revealed disease causing mutations associated with CPC and genitourinary diseases which could close the gaps of surgery in bringing intervention in therapies.

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Re-analysis of whole-exome sequencing data reveals a novel splicing variant in the SLC2A1 in a patient with GLUT1 Deficiency Syndrome 1 accompanied by hemangioma: a case report

BMC Medical Genomics ◽

10.1186/s12920-021-01045-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Tugce Bozkurt ◽

Yasemin Alanay ◽

Ugur Isik ◽

Ugur Sezerman

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Glucose Transporter ◽

De Novo ◽

Deficiency Syndrome ◽

Splicing Variant ◽

Whole Exome ◽

Wide Range ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

Abstract Background GLUT1 Deficiency Syndrome 1 (GLUT1DS1) is a neurological disorder caused by either heterozygous or homozygous mutations in the Solute Carrier Family 2, Member 1 (SLC2A1) gene. SLC2A1 encodes Glucose transporter type 1 (GLUT1) protein, which is the primary glucose transporter at the blood–brain barrier. A ketogenic diet (KD) provides an alternative fuel for brain metabolism to treat impaired glucose transport. By reanalyzing exome data, we identified a de novo heterozygous SLC2A1 variant in a girl with epilepsy. After reversed phenotyping with neurometabolic tests, she was diagnosed with GLUT1DS1 and started on a KD. The patient's symptoms responded to the diet. Here, we report a patient with GLUT1DS1 with a novel SLC2A1 mutation. She also has a hemangioma which has not been reported in association with this syndrome before. Case presentation A 5-year 8-month girl with global developmental delay, spasticity, intellectual disability, dysarthric speech, abnormal eye movements, and hemangioma. The electroencephalography (EEG) result revealed that she had epilepsy. Magnetic resonance imaging (MRI) showed that non-specific white matter abnormalities. Whole Exome Sequencing (WES) was previously performed, but the case remained unsolved. The re-analysis of WES data revealed a heterozygous splicing variant in the SLC2A1 gene. Segregation analysis with parental DNA samples indicated that the variant occurred de novo. Lumbar puncture (LP) confirmed the diagnosis, and the patient started on a KD. Her seizures responded to the KD. She has been seizure-free since shortly after the initiation of the diet. She also had decreased involuntary movements, her speech became more understandable, and her vocabulary increased after the diet. Conclusions We identified a novel de novo variant in the SLC2A1 gene in a patient who previously had a negative WES result. The patient has been diagnosed with GLUT1DS1. The syndrome is a treatable condition, but the differential diagnosis is not an easy process due to showing a wide range of phenotypic spectrum and the overlapping symptoms with other neurological diseases. The diagnosis necessitates a genomic testing approach. Our findings also highlight the importance of re-analysis to undiagnosed cases after initial WES to reveal disease-causing variants.

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Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – A case report

10.21203/rs.2.307/v3 ◽

2019 ◽

Author(s):

Sofia Thunström ◽

Markus Axelsson

Keyword(s):

Case Report ◽

De Novo ◽

Age Of Onset ◽

De Novo Mutation ◽

Missense Mutations ◽

Case Presentation ◽

Whole Exome ◽

Demyelinating Peripheral Neuropathy ◽

The Brain ◽

Multiple Cysts

Abstract Background: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. Case presentation: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686T>G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. Conclusions: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.

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